Irritable bowel syndrome (IBS) is a syndrome which causes chronic symptoms such as abdominal pain, bloating, and the like, bowel movement disorders such as diarrhea, constipation, and the like, defecation trouble, defecation straining, and the like. It is caused by functional abnormality of the lower digestive tract, mainly the large intestine, despite the absence of organic disorders such as inflammation, tumors, and the like, and is classified based on the conditions of stool into diarrhea-predominant, constipation-predominant, and alternating IBS which alternately repeats diarrhea and constipation. IBS is a disease which has a relatively high frequency occupying from 20 to 50% of bowel disease patients who consult outpatient cares, which is predominant in females with a male to female ratio of 1:2 regardless of race, and which has a high prevalence rate in the younger generation. Since mental stress correlates strongly with the state of the disease, it is regarded as a representative stress-related somatic disease and it is said that the stress management is important for the improvement of symptoms. Actually, it is known that abnormal motility of gastrointestinal tract is significantly accelerated and the symptoms are aggravated when emotional stress is applied to IBS patients. In addition, since the symptoms continue, a vicious circle is likely to form in which increased patient anxiety further aggravates the symptoms.
As the drug therapy of IBS, an anticholinergic is used for abdominal pain, and a tricyclic antidepressant for the improvement of pain threshold value reduction in the digestive tracts, and for the improvement of abnormal bowel motility, a stegnotic, a drug for controlling intestinal function, and the like in the case of diarrhea, and a saline cathartic and the like in the case of constipation, however these are merely symptomatic therapies and their effects are not clear. As an agent from which effects can be expected for both diarrhea and constipation, there is polycarbophil calcium, which regulates the hardness of feces by gelating in the intestines, however it exerts very limited effects because not only there is a bloating at the initial stage of its administration but also it requires time to exhibit the effects. Anxiolytics and antidepressants are used when anxiety and tension are considerably increased due to stress, however they are administered at a dose lower than the dose in the psychiatric field, so that there are cases in which the mental symptoms are not improved or cases in which these are improved but they do not exhibit any effects on the bowel movement disorder. Generally, among the symptoms of IBS, anxiolytics are effective for diarrhea and abdominal pain in some cases, but they have a tendency to exhibit little effect on constipation.
There are a 5-HT3 receptor antagonist alosetron and a 5-HT4 receptor agonist tegaserod as the agents, which have been drawing attention in recent years, and they are used in the diarrhea-predominant and the constipation-predominant, respectively. These agents improve the bowel movement by regulating the movement of intestines, and exhibit an effect quickly. However, though alosetron shows a relatively high improving rate of from 40 to 60% for abdominal symptoms and diarrhea, constipation occurs in 30 to 35% of the patients and it causes ischemic colitis (including mortal cases) as a serious side effect, so that its use is limited (Non-Patent Document 1). In addition, it cannot be said that the effect of tegaserod on the constipation-predominant is sufficient, and there is a possibility of causing tachyphylaxis (a phenomenon in which resistance is generated when a drug is repeatedly administered within a short period of time).
Apropos, when the living body receives a stress, it generates a hypothalamic-pituitary-adrenal system (HPA system) reaction, in which an adrenocorticotropic hormone (ACTH) is released through the secretion of a stress-related substance from the hypothalamus and a subsequent action upon the anterior hypophysis, and the ACTH released into the blood secretes corticosterone from the adrenal cortex, and thereby shows various stress responses such as increase in the blood pressure and the like. As the stress-related substance, corticotropin releasing hormone (CRH), bombesin (BB)/gastrin releasing peptide (GRP), vasopressin, neuropeptide Y, substance P, neurotensin, and the like are known. Secretion of these substances from the hypothalamus is accelerated when a stress is applied to an animal. Particularly regarding the CRH, it has been reported that it reinforces ACTH release and large bowel movement when administered to IBS patients (Non-Patent Document 2).
The bombesin/GRP as one of the stress-related substances is a brain-gut peptide and expresses various physiological actions via bombesin receptors. The bombesin receptor is classified into 3 subtypes of BB1, BB2 and BB3/BRS3 (bombesin receptor subtype-3), and as intrinsic ligands of mammals for the BB1 and BB2 receptors, neuromedin B and GRP have been identified respectively. It has been reported that the GRP and BB2 receptors are present ubiquitously in the brain, the digestive tracts, and the like, but GRP is markedly increased in the amygdala and hypothalamus when stress is applied to an animal (Non-Patent Document 3). In addition, it has been reported also that a BB2 receptor antagonist inhibits the increase in ACTH when administered into the cerebral ventricle in a restraint stress-added rat (Non-Patent Document 4).
As the role of the GRP/BB2 receptor in the digestive tract functions, it has been reported that it enhances the contraction in isolated human and rabbit ileum longitudinal muscle specimens (Non-Patent Documents 5 and 6), and enhances the water secretion in guinea pigs with the coexistence of a vasoactive intestinal peptide (VIP) (Non-Patent Document 7). In addition, it has been reported that BB2 receptor antagonists including RC-3095 that is a peptidic BB2 receptor antagonist, is effective for an abnormal bowel motility in a stress-induced defecation model. It has also been reported that, using an abdominal muscle contraction reaction as the index, RC-3095 is effective for an abdominal symptom in an abdominal pain model induced by large intestinal distension. Accordingly the BB2 receptor antagonist shows excellent efficacy on both the abdominal symptom and abnormal bowel motility (Patent Document 1).
As shown above, the BB2 receptor antagonist is expected to be a therapeutic agent for IBS, showing excellent efficacy on both the abdominal symptom and abnormal bowel motility.
Furthermore, since the bombesin/GRP also has a function as a cell growth factor and the expression of the GRP/BB2 receptor is increased in various cancer cells of lung cancer, prostate cancer, and the like, the efficacy of RC-3095 has been reported in a large number of antitumor tests (Non-Patent Documents 8 to 10). From this viewpoint, the BB2 receptor antagonist can also be expected to be effective against various cancers.
The tetrahydroisoquinolin-1-one derivative has been reported in Patent Documents 2 to 4.
Patent Document 2 describes that a 3,4-dihydroisoquinolin-1-one derivative represented by the following formula (A) has a caspase activating action and an apoptosis inducing action, and is effective for cancers, autoimmune diseases, rheumatoid arthritis, inflammatory bowel syndrome, psoriasis, and the like. However, there is no description of its antagonistic action on a bombesin type 2 receptor or of its efficacy regarding IBS.

(for the symbols in the formula, refer to the publication)
Patent Document 3 describes that a tetrahydroisoquinolin-1-one derivative represented by the following formula (B) is a ligand of an HDM2 protein, has an apoptosis inducing activity and a proliferation inhibitory activity, and is effective against cancers. However, there is no description of its antagonistic action on a bombesin type 2 receptor or of its efficacy regarding IBS.

(for the symbols in the formula, refer to the publication)
Patent Document 4 describes that a tetrahydroisoquinolin-1-one derivative represented by the following formula (C) is a neurotensin-2 (NT-2) receptor antagonist and is effective against pain. However, for R5 corresponding to R1 of the present invention, there is no description on the R1 group of the present invention. In addition, there is no description of its antagonistic action on a bombesin type 2 receptor or of its efficacy regarding IBS.

(wherein R5 means (C1-C8)alkyl which is optionally substituted with a group selected from trifluoromethyl, halogen, saturated or partially unsaturated (C3-C8)cycloalkyl, and (C6-C10)aryl. For the other symbols, refer to the publication.)
The compounds described in the following Tables 1 to 11 below are reported as Catalog Compounds. However, there is no description of the antagonistic action on a bombesin type 2 receptor and the efficacy for IBS, of these compounds. Further, in the following Tables, the abbreviations below are used. Me: Methyl, Et: Ethyl, iPr: Isopropyl, nBu: Normal Butyl, Ph: Phenyl.
TABLE 1  CAS RegistryNo.RaRbN—931939-66-1 931315-65-0 902607-43-6Me2N—902450-09-3Ph—(CH2)2—NH—891914-00-4PhCH2—NH— 891913-84-1 891913-76-1 891913-68-1 891913-28-3 891913-04-5 891912-88-2EtNH— 891912-80-4
TABLE 2891912-64-4 891912-56-4 891912-48-4 891912-40-6 891912-16-6 891912-08-6 891912-00-8 891911-84-5 891911-60-7 891911-52-7 891911-44-7 891911-36-7
TABLE 3891911-29-8 891911-22-1 891911-07-2 891910-93-3 891910-86-4 891910-72-8 891910-65-9 891910-58-0 891910-23-9 891910-07-9 891909-99-2 891909-91-4EtO—(CH2)3—NH— 891909-83-4
TABLE 4891909-75-4 891909-67-4 891909-59-4iPrO—(CH2)3—NH— 891909-51-6 891909-27-6PhN(Et)—(CH2)3—NH— 891909-11-8 891909-03-8 891908-95-5 891908-55-7Et2N— 891907-99-6 891907-91-8 891907-83-8 891907-75-8 891907-43-0MeO—(CH2)3—NH—891907-35-0nBuNH—891907-27-0iPrNH— 891907-19-0 891907-11-2MeO—(CH2)2—NH—
TABLE 5891907-03-2 891906-95-9 891906-87-9 891906-79-9 891906-71-1 891906-55-1 891906-39-1 891905-75-2 891904-87-3
TABLE 6 CAS Registry No.RaRbN—685520-62-1 685520-61-0 442858-62-0EtO2C—CH2—NH— 442858-61-9 442858-27-7MeO2C—(CH3)2—NH—442858-05-1MeO2C—CH2—NH— 442858-04-0 442857-76-3 442857-73-0 442856-86-2 442856-85-1 442856-80-6Et2N—
TABLE 7442856-71-5 442856-34-0 442856-31-7 442856-30-6 442856-29-3iPrNH— 442856-28-2 442856-17-9 442856-15-7PhN(Et)-(CH2)3—NH— 442855-08-5 442854-93-5 442854-92-4 442854-57-1MeO—(CH2)2—NH— 442854-41-3
TABLE 8 CAS Registry No.RaRbN—685520-63-2 442859-46-3 442859-42-9 442859-40-7 442859-39-4 442859-38-3 442859-36-1 442859-27-0 442859-26-9
TABLE 9442859-25-8 442859-20-3Et2N— 442859-13-4 442859-12-3 442859-11-2MeO—(CH2)3—NH—442859-09-8nBuN(Et)— 442859-06-5 442859-05-4nBuNH— 442859-03-2 442859-02-1EtO2C—CH2—NH—442859-01-0MeO—(CH2)2—NH—442858-99-3nBuN(Me)NH— 442858-98-2 442858-93-7 442858-91-5PhCH2N(Me)— 442858-86-8 442858-79-9
TABLE 10442858-77-7 442858-76-6 442858-72-2 442858-67-5 442858-56-2iPrNH— 442858-55-1
TABLE 11 CAS Registry No.RaRbN—442888-72-4 442888-70-2 442888-60-0 442888-49-5 442888-41-7 442888-39-3 442888-37-1 442888-35-9
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